CN104666248B - 提供立即释放模式和持续释放模式双重作用的吸入制剂 - Google Patents
提供立即释放模式和持续释放模式双重作用的吸入制剂 Download PDFInfo
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- CN104666248B CN104666248B CN201510089105.3A CN201510089105A CN104666248B CN 104666248 B CN104666248 B CN 104666248B CN 201510089105 A CN201510089105 A CN 201510089105A CN 104666248 B CN104666248 B CN 104666248B
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Abstract
本发明涉及提供立即释放模式和持续释放模式双重作用的吸入制剂,具体地,涉及配制立即释放和持续释放抗感染药物的方法和递送这种抗感染药物用于治疗呼吸道感染和其它医学状况,以及与这些有关所用的装置和制剂。
Description
本申请为国际申请PCT/US2007/022424于2009年4月23日进入中国国家阶段、申请号为200780039587.5、发明名称为“提供立即释放模式和持续释放模式双重作用的吸入制剂”的分案申请。
技术领域
本发明涉及吸入用药物组合物,诸如用于治疗由许多微生物引起的呼吸道感染。特别地,本发明涉及双相释放制剂,其提供了通过吸入被递送的药物诸如抗感染药物的立即释放和持续释放用于治疗囊性纤维化。
背景技术
呼吸道感染由许多微生物引起。感染对卫生保健公众具有持久的多个后果,包括增加的治疗负担和费用,并且为患者带来更具有侵入性的治疗样式并且可能导致重病以至死亡。如果可以获得改善的治疗样式来提供预防性治疗从而避免易受影响的患者获得呼吸道感染以及增加对已经感染有微生物的患者中的感染的根除速率或有效性将是有益的。
特别地,囊性纤维化(CF)是其中患者经常获得持久的或顽强的呼吸道感染的疾病的一个实例。CF是危急生命的遗传疾病,其以每2,500名活产儿中约有1名的频率影响约30,000美国人(Fitzsimmons SC,1993)。囊性纤维化是指胰腺内的特征性的疤痕(纤维化)和孢囊形成,首次在20世纪30年代被认识。每年有约1,000例新的CF病例被确诊。超过80%的患者在三岁时被确诊,然而,几乎10%的新被确诊的病例在18岁以上。
主要的CF缺陷表现为由囊性纤维化跨膜传导调节蛋白(CFTR)介导的离子转运改变,该囊性纤维化跨膜传导调节蛋白是调节在分泌上皮顶膜处的环AMP介导的氯离子传导的蛋白质(Schroeder SA等人,1995)。具体而言,正常的细胞内氯离子释放进入细胞外液不能应答正常的cAMP升高。这种氯离子释放变弱导致周围呼吸粘膜和肠粘膜管路脱水和汗腺的钠再吸收变弱。这种粘膜脱水结合炎性和感染性副产物,产生了浓稠的和粘滞的粘液,其阻塞和损害气道。对CF症状进行迅速的攻击性的治疗可以延长罹患这些疾病的患者的寿命。
尽管大部分无CF的人具有CFTR基因的两个工作拷贝,仅一个需要用于预防囊性纤维化。当两个基因都不正常工作时CF才发展。因此,CF被认为是常染色体隐性疾病。与该疾病有关,存在超过1,500种不同的遗传突变(CFTR突变数据库(2006)),因此使得纯合的和杂合的筛选程序变得困难(Zielenski J等人,1995)。然而,约三分之二的突变被发现是ΔF508,使得其成为最常见的CF突变(CF Genetic Analysis Consortium,1994)。
目前实行的CF治疗依赖于疾病的阶段和所牵涉的器官的不同而异。清除得自肺的粘液是每日CF治疗方案的重要部分。胸物料疗法是一种气道清除形式,其要求对背和胸实施有力的撞击(通过使用杯手形)以从肺逐出浓稠的粘液。其它的气道清除形式可在用于促进粘液清除的机械工具的帮助下进行。其它类型的治疗包括:一种吸入式粘液溶解剂,表现为降低肺感染数和改善肺功能(Hodson M,1995);(用于吸入的妥布霉素溶液),一种气雾化的氨基糖苷类抗菌素,用于治疗肺感染并还显示为改善肺功能(Weber A等人,1994);和口服阿奇霉素,一种大环内脂类抗菌素,表现为降低呼吸恶化数和肺功能下降速率(Wolter J等人,2002)。
正如以上的讨论,在囊性纤维化(CF)患者中的铜绿假单胞菌感染的高集落化速率和应对这一感染的挑战迫使寻找安全的和有效的抗生素。目前,使用氨基糖苷类结合β-内酰胺类或喹诺酮类抗生素的治疗是标准疗法。在包括520名具有中度到重度CF的患者的临床研究中进行的为期96周的试验表明,接受吸入的妥布霉素的患者的住院时间少了25到33%天并经历肺功能的显著增加(Moss RB,2001)。这些结果显示了吸入式抗生素用于治疗CF的有效性。然而,耐药株特别是铜绿假单胞菌的发展是借助吸入长期递送气雾化抗生素的一个主要担忧(LiPuma JJ 2001)。
尽管阿奇霉素针对金黄色葡萄球菌(Staphylococcus aureus),流感嗜血杆菌(Haemophilus influenzae)和肺炎链球菌(Streptococcus pneumoniae)具有活性,但是不直接针对铜绿假单胞菌(Pseudomonas aeruginosa),伯克霍尔德杆菌(Burkholderiacepacia)或其它革兰氏阴性非发酵菌(Lode H等人,1996)。妥布霉素针对铜绿假单胞菌具有活性,然而,在3个月的持续治疗后具有耐药性分离物的患者数目从~10%增加到80%(Smith AL等人,1989)已经导致在28天中止治疗后继续28天持续治疗的间歇性给药方案。即使使用间歇性吸入式的妥布霉素治疗,具有多耐药性铜绿假单胞菌的患者的百分数在治疗18个月后从基线的14%增加到23%(LiPuma JJ,2001)。开发一种以持续方式递送抗感染药物治疗并仍抑制耐药性分离物的出现的治疗方式提供了一种改善的治疗样式。值得注意的是,慢性铜绿假单胞菌气道感染一直是CF患者的发病率和死亡率的根本原因。当患者经历肺恶化时,使用抗假单胞菌治疗,通常包括β-内酰胺类和氨基糖苷类,可导致临床改善和细菌负荷下降。然而,感染的根除是十分罕见的。
在CF气道中,铜绿假单胞菌最初具有非类粘蛋白表型,但是最终产生类粘蛋白胞外多糖并组构成为生物膜,其表明气道感染从急性发展成慢性。在生物膜中的细菌由于缺氧环境而生长非常迟缓,并且对抗微生物剂具有固有的耐药性,因为固着细胞比浮游细胞生长更不易受影响。已据报道,生物膜细胞对抗菌药的耐药性高至少500倍(Costerton JW等人,1995)。因此,类粘蛋白表型的转变和生物膜的产生通过保护细菌抵御宿主防御并干扰抗生素向细菌细胞的递送而使得铜绿假单胞菌在慢性感染的CF患者中的持续存在作出贡献。
尽管已经进行了许多努力以改善CF个体的护理和治疗,并且平均寿命已有增加,但是CF人群的平均存活年龄仅达到30多岁(CF Foundation web site,2006)。因此,持续需要改善的抗感染药物的制剂,特别是用于吸入给药的改善制剂。本发明解决了这一需要。
环丙沙星是氟喹诺酮类抗生素,其适应症为用于治疗由铜绿假单胞菌引起的下呼吸道感染,铜绿假单胞菌在囊性纤维化患者中是常见的。环丙沙星是广谱药物,并且除了对抗铜绿假单胞菌之外还对抗若干种其它类型的革兰氏阴性和革兰氏阳性细菌。其通过抑制拓扑异构酶II(DNA回旋酶)和拓扑异构酶IV起作用,这些酶是细菌复制、转录、修复和重组所需要的酶。这一作用机理与青霉素类、头孢菌素类、氨基糖苷类、大环内酯类和四环素类的作用机理不同,因此,对这类药物具有耐药性的细菌可能对环丙沙星是敏感的。因此,发展为对氨基糖苷类妥布霉素(TOBI)具有耐药性的CF患者仍可采用环丙沙星进行治疗。在环丙沙星和其它类别的抗微生物之间没有已知的交叉耐药性。
尽管环丙沙星具有吸引人的抗菌性质,但是环丙沙星的确产生讨厌的副作用,诸如GI不耐性(呕吐、腹泻、腹部不适),以及眩晕、失眠、兴奋性和焦虑程度增加。明确需要改善的治疗方案,其可被长期使用而不导致这些不适合的副作用。
递送作为吸入气雾剂形式的环丙沙星通过将药物的递送和起效限定在呼吸道(主要感染部位)内而解决了这些担忧。
目前没有被官方批准用于人用的能够将抗生素靶向递送到主要感染区域的环丙沙星的气雾化形式。这部分地是因为药物的溶解性差和苦味阻碍了适于吸入的制剂的开发。另外,环丙沙星的组织分布如此迅速使得药物在肺内的渚留时间太短,从而相对于药物经口或IV途径给药不能提供另外的治疗益处。
磷脂媒介物作为药物递送系统在1965作为“脂质体”被重新发现(Bangham等人,1965)。许多活性药物成分(APIs)的治疗性质可通过并入到脂质体药物递送系统内得以改善。通用术语脂质体涵盖了各式各样的结构,但是一般所有的脂质体都由一个或多个脂质双分子层组成,所述脂质双分子层围成水性空间,药物可被包封在这一水性空间内。在这一计划中采用的脂质体是药物递送领域中已知的大单层脂质体(LUV),其是用于IV给药的优选的脂质体结构。
脂质体包封通过许多机制改善了生物药学特征,包括改变的药物药代动力学和生物分布,药物从载体的持续释放,向患病部位的增强的递送,和保护活性药物物质免于降解。抗癌药多柔比星柔红霉素抗真菌药两性霉素B和苯并卟啉的脂质体制剂是在过去的十年期间被成功引入美国、欧洲和日本市场的产品。另外,许多二代产品经历了后期临床试验,包括Inex的长春新碱硫酸盐脂质体注射剂(VSLI)。基于脂质的载体的被证明的安全性和效力使得它们成为药物制剂的吸引人的候选物。
因此,与目前的环丙沙星制剂相比,脂质体环丙沙星气雾剂将提供以下若干益处:1)更高的药物浓度,2)借助于在感染部位处的持续释放具有增加的药物渚留时间,3)降低的副作用,4)增加的适口性,5)更好地渗透进入细菌,和6)更好地渗透进入被细菌感染的细胞。先前已显示用脂质体包封的氟喹诺酮类抗生素的吸入可有效治疗肺感染。在土拉菌病(F.tularensis)的小鼠模型中,用脂质体包封的氟喹诺酮类抗生素通过增加存活而显示了优于游离的或未包封的氟喹诺酮类(CA2,215,716,CA2,174,803和CA2.101.241)。
另一个申请EP1083881B1描述了包含药物-缀合物的脂质体,该药物-缀合物包括与氨基酸共价连接的喹诺酮化合物。又一个申请美国公报No.20004142026还描述了用脂质体包封的抗生素的使用和可能给药较低剂量的用脂质体包封的抗感染药物,该较低剂量是游离的未包封抗感染药物剂量的十分之一或百分之一。
还报道了在生物膜深度内存在亚抑制浓度的抗生素提供了对更具耐药性的表型的发展具有选择性压力(Gilbert P等人,1997)。这可能部分地是由于抗生素不能充分地穿透外被多糖所致。
发明内容
本发明的一方面是粒子的气雾化双相组合物。该粒子包括游离药物(例如抗感染化合物),该药物未被包封并且可以是环丙沙星。该粒子另外包括脂质体,该脂质体包封了诸如也可以是环丙沙星的抗感染化合物的药物。游离的药物和用脂质体包封的药物被包含在被配制用于气雾化递送的可药用赋形剂中。该粒子可另外包括附加治疗剂,该附加治疗剂可以是游离的和/或位于脂质体内并且其可以是与第一药物不同的任何药学活性药物。
本发明的一方面是包括脂质体的制剂,脂质体借助于气雾剂形式被递送到人患者的肺中,该脂质体包括游离的环丙沙星和被包封的环丙沙星或其它抗感染药物。该脂质体可以是单层或多层的,并且可以具有生物粘附性,包含诸如透明质酸的分子。在该组合物还可包含除了游离的氟喹诺酮类抗生素和用脂质体包封的抗感染药物之外的至少一种治疗剂。该治疗剂可以是游离药物或被包封的药物,其与可用于直接吸入人肺的可药用载体一起存在。
其它的药物可包括降低粘液粘弹性的酶诸如脱氧核糖核酸酶或其它粘液溶解剂,包括羊毛硫抗生素诸如耐久霉素在内的上调氯离子通道或增加穿过细胞的离子流的化学品,包括上皮钠通道(ENaC)抑制剂或P2Y2激动剂诸如地纽福索在内的促进水合或粘膜纤毛清除的药剂,包括α-1抗胰蛋白酶(AAT)在内的弹性酶抑制剂,支气管扩张药,甾族化合物,N-乙酰半胱氨酸,干扰素γ,干扰素α,增强抗生素对抗生物膜细菌的活性的药剂诸如水杨酸钠(Polonio RE等人,2001),或本领域技术人员已知的抗生素。气道的炎症和收缩也与囊性纤维化及其治疗有关。因此,支气管扩张药诸如β2-肾上腺素能受体激动剂和抗毒蕈碱药物,以及抗炎药,包括吸入式皮质甾类,非甾体抗炎药,白细胞三烯受体拮抗体或白细胞三烯合成抑制剂,及其它,也可与抗感染药物组合使用。
本发明的另一个方面是治疗患者的囊性纤维化的方法,该方法包括对患者给予包括被包封在脂质体内的抗感染药物如环丙沙星的制剂。该制剂优选通过吸入到患者进行给药。
根据本发明的另一个方面,既包括游离的抗感染药物又包括被包封的抗感染药物的制剂提供了抗感染药物在肺内的最初高治疗水平从而克服障碍以根除难以治疗的生物膜细菌,同时保持抗感染药物随时间的持续释放。尽管对生物膜耐药性的一些方面缺乏了解,但是认为主要机理与以下有关:(i)生物膜内的营养环境的改变和生长速率的抑制;(ii)胞外聚合物基质及其构成与抗微生物药之间的直接相互作用影响了扩散和可利用性;和(iii)生物膜/连接的特异性表型的发展(Gilbert P等人,1997)。立即释放抗感染药物例如环丙沙星的意图是由此迅速地增加抗生素在肺内在难以根除的生物膜细菌周围的浓度到治疗水平,从而克服抗生素向生物膜及其内部的扩散速率较低的挑战。持续释放抗感染药物例如环丙沙星用于维持抗生素在肺内的治疗水平从而在更长的时帧内提供持续治疗,增加效力,降低给药频率并降低耐药集落形成的可能性。
根据本发明的另一个方面,高水平的抗感染药物的立即释放可允许外被多糖的渗透增强。抗感染药物的持续释放可确保抗感染药物决不会降低到亚抑制浓度下并因此降低形成对抗感染药物的耐药性的可能性。
本发明的这些和其它目的、优点和特征在本领域技术人员阅读了以下更充分描述的制剂和方法的细节之后变得显而易见。
附图说明
本发明的各方面和实施方案当结合附图进行阅读时从以下的详细说明被更好地理解。需要强调的是,根据惯例,附图的各个特征不是按比例的。相反地,为了清楚目的,各个特征的尺寸被任意地放大或缩小。在附图中包括以下图:
图1是用于吸入的脂质体环丙沙星的制造流程图表(HSPC/Chol-10 L批)。
图2是表示在第0天用装载铜绿假单胞菌的琼脂糖小珠感染后小鼠累积存活率的图表。小鼠从第2天开始到第9天结束,每天使用三种浓度(100%,空心菱形;33%实心正方形;或10%,空心三角形)之一的环丙沙星(药物)的脂质体制剂进行鼻内治疗。稀释剂用作对照(实心圈)。在第10天处死存活的小鼠。
发明的详细说明
在描述配制包封有环丙沙星的脂质体和递送这种脂质体用于预防和/或治疗囊性纤维化和其它医学状况的方法,和与这些有关的装置和制剂之前,可理解的是本发明不局限于所述的具体的方法、装置和制剂,因为这些方法、装置和制剂当然可改变。还可理解的是,本文使用的术语的目的仅仅是用于描述具体实施方案的目的,而不意在对本发明的范围构成限制,本发明的范围仅仅由权利要求书进行限定。
当提供了值的范围时,可理解,每个居中值,到下限单位的十分之一,除非上下文清楚地指出并非如此,还特别地公开了在该范围的上限和下限之间。在所述范围内的任何所述值或居中值之间的每个更小范围和在该所述范围内的任何其它所述值或居中值被包含在本发明中。这些更小范围的上限和下限可独立地被包括或不包括在该范围内,并且其中任一个限度被包含、或两个限度都不或都被包含在更小的范围内的每个范围也被包含在本发明中,根据任何在所述范围内的具体被排除的限度而定。当所述范围包括限度之一或二者时,不包括这些被包括的限度之一或二者的范围也被包含在本发明中。
除非另有说明,否则本文使用的全部的专业术语和科技术语具有本发明所属领域内的普通技术人员通常已知的含义。尽管可以使用与本文所述那些是相似的或等价的方法和材料用于实践或试验本发明,但是现在描述优选的方法和材料。本文提及的全部公开作为参考被并入本文用于公开和描述与所引述公开有关的方法和/或材料。
必须指出,在本文和权利要求书中使用的单数形式“一”、“一个”、“一种”包括复数形式,除非上下文清楚地指出并非如此。因此,例如,提到的“制剂”包括该制剂的复数形式并且提到的“方法”包括对一种或多种方法及其本领域技术人员已知的等价物的所指等等。
本文论述的出版物仅用于提供它们在本申请的提交日之前的公开。本文中没有地方可被认为是承认了本发明可根据在本发明之前的这些出版物是可预料的。另外,提供的公布日期可能不同于现行的出版日期,这可独立地进行证实。
本文使用的抗感染药物是指对抗感染诸如细菌、病毒、真菌、分枝杆菌或原生动物感染的药剂。
被本发明涵盖的抗感染药物包括但不限于喹诺酮类(诸如萘啶酸,西诺沙星,环丙沙星和诺氟沙星等等),磺酰胺类(例如磺胺,磺胺嘧啶,磺胺甲恶唑(sulfamethaoxazole),磺胺异噁唑,乙酰磺胺等等),氨基糖苷类(例如链霉素,庆大霉素,妥布霉素,氨基羟丁基卡那霉素,奈替米星,卡拉霉素等等),四环素类(诸如金霉素,土霉素,甲烯土霉素,强力霉素,米诺环素等等),对氨基苯甲酸,二氨基嘧啶类(诸如甲氧苄氨嘧啶,通常与新诺明结合使用,吡嗪酰胺等等),青霉素类(诸如青霉素G,青霉素V,氨苄西林,阿莫西林,巴氨西林,羧苄西林,卡茚西林,替卡西林,阿洛西林,美洛西林,哌拉西林等等),青霉素酶耐药性青霉素类(诸如甲氧西林,苯唑西林,氯唑西林,双氯西林,萘夫西林等等),第一代头孢菌素类(诸如头孢羟氨苄,头孢氨苄,头孢拉啶,头孢噻吩,头孢匹林,头孢唑林等等),第二代头孢菌素类(诸如头孢克洛,头孢孟多,头孢尼西,头孢西丁,头孢替坦,头孢呋肟,头孢呋新酯,头孢它唑(cefinetazole),头孢丙烯,氯碳头孢,头孢雷特等等),第三代头孢菌素类(诸如头孢匹罗,头孢哌酮,头孢噻肟,头孢唑肟,头孢曲松,头孢他啶,头孢克肟,头孢泊肟,头孢布烯等等),其它的β-内酰胺类(诸如亚胺培南,美罗培南,氨曲南,克拉维酸,舒巴坦,三唑巴坦等等),β-内酰胺酶抑制剂(诸如克拉维酸),氯霉素,大环内酯类(诸如红霉素,阿奇霉素,克拉霉素等等),林可霉素,克林霉素,大观霉素,多粘菌素B,多粘菌素类(诸如多粘菌素A、B、C、D、E1(粘菌素A)或E2粘菌素B或C等等),粘菌素,万古霉素,杆菌肽,异烟肼,利福平,乙胺丁醇,乙硫异烟胺,氨基水杨酸,环丝氨酸,卷曲霉素,砜类(诸如氨苯砜,阿地砜钠等等),氯法齐明,沙利度胺,或任何其它的可用脂质包封的抗菌药。抗感染药物可包括抗真菌药,包括多烯类抗真菌药(诸如两性霉素B,制霉菌素,那他霉素等等),氟胞嘧啶,咪唑类(诸如咪康唑,克霉唑,益康唑,酮康唑等等),三唑类(诸如伊曲康唑,氟康唑等等),灰黄霉素,特康唑,布康唑,环吡酮,环吡酮胺,卤普罗近,托萘酯,萘替芬,特比萘芬,或任何其它的可用脂质包封的或复合的抗真菌药及其可药用盐及其组合。讨论和实施例主要直接针对环丙沙星,但是本申请的范围并不意在受到该抗感染药物的限制。可使用药物组合。
被本发明涵盖的支气管扩张药包括但不限于β2-肾上腺素能受体激动剂(诸如沙丁胺醇,班布特罗,沙丁胺醇,沙美特罗,福莫特罗,福莫特罗,左旋沙丁胺醇,丙卡特罗,茚达特罗,卡莫特罗,米威特罗(milveterol),丙卡特罗,特布他林等等),和抗毒蕈碱药物(诸如曲司铵,异丙托品,格隆铵,阿地铵等等)。可使用药物组合。
被本发明涵盖的抗炎药包括但不限于吸入式皮质甾类(诸如倍氯米松,布地奈德,环索奈德,氟替卡松,艾泼诺,莫米松等等),白细胞三烯受体拮抗体和白细胞三烯合成抑制剂(诸如孟鲁司特,齐留通,异丁司特,扎鲁司特,普仑司特,阿美卢班,泰鲁司特等等),环加氧酶抑制剂(诸如布洛芬,酮洛芬,酮咯酸,吲哚美辛,萘普生,扎托洛芬,氯诺昔康,美洛昔康,塞来昔布,鲁米昔布,依托昔布,吡罗昔康,安吡昔康,辛诺昔康,双氯芬酸,联苯乙酸,氯诺昔康,美沙拉秦,三氟柳,替诺立定,艾拉莫德,帕米格雷等等)。可使用药物组合。
本文使用的“制剂”是指用脂质体包封的抗感染药物,具有任何赋形剂或另外的活性成分,为干粉形式或为悬浮或溶解在液体中的形式。
术语“受试者”、“个体”、“患者”和“宿主”在本文可互换使用并且是指任何脊椎动物,特别是指任何哺乳动物,最特别地包括人类受试者、农畜和哺乳动物宠物。受试者可以是但不必然地处在卫生保健专业人员如医生的护理下。
“稳定的”制剂是指其中的蛋白质或酶在储存时和当暴露在较高温度下时基本上保持其物理和化学稳定性和完整性的制剂。用于测量肽稳定性的各种分析技术是本领域中已知的并且综述在以下文献中:Peptide and Protein Drug Delivery,247-301,VincentLee编,Marcel Dekker,Inc.,New York,N.Y.,Pubs.(1991)和Jones,A.(1993)Adv.DrugDelivery Rev.10:29-90。稳定性可以在选定温度下测量持续选定时段。
“哺乳动物”对于治疗目的是指任何被归类为哺乳动物中的动物,包括人、家畜和农畜,以及动物园动物、运动玩赏用动物,诸如狗、马、猫、牛等。优选地,哺乳动物是人。
“病症”是指任何从用本发明要求保护的方法和组合物的治疗中受益的任何病况。
I.包含环丙沙星的脂质体的产生
根据本发明的各方面,提供了通过将环丙沙星和其它抗感染药物包封在脂质体内而配制环丙沙星和其它抗感染药物的方法。由生物相容的和生物可降解的天然存在的材料组成的脂质体用于包封生物学活性材料用于许多目的。已经开发了制备具有许多层、大小、表面电荷和组成的脂质体和在该脂质体内包封药物的许多方法,其中有一些已经按比例放大到工业水平。脂质体可被设计用于作为持续释放药物储库并且在某些应用中帮助药物穿过细胞膜。
脂质体的持续释放性质可通过脂质膜的性质以及通过在脂质体组合物内包含其它的赋形剂进行调节。多年以来对脂质体技术的广泛研究已经获得了基于脂质体制剂的组成对药物释放速率进行合理的预测。药物释放速率主要依赖于磷脂的性质例如氢化(--H)或未氢化(--G)或磷脂/胆固醇的比率(这一比率越高,则释放速率越快)、活性成分的亲水性/亲脂性及脂质体的制造方法的不同而异。
制造生物粘附性脂质体的方法可见于U.S.5,401,511(其作为参考被全文并入本文)以及其中所引述的专利和公报,其描述了脂质体和脂质体的制造方法。最近几年中,已经成功地对脂质体结合了不同的物质。例如,已经研究了将糜蛋白酶结合到脂质体作为用于将物质结合到脂质体表面的模型。考虑到包括抗体、糖蛋白和凝集素在内的物质已被结合到脂质体表面以试图比较脂质体的靶向特异性。
脂质体表面上用于共价结合的离散位点的数目和表面密度受脂质体制剂和脂质体类型支配。脂质体表面还具有非共价结合的位点。共价结合是优选的,因为非共价结合可能导致在给药部位处所考虑的物质与脂质体发生分离,因为脂质体和目标位点的生物粘附性配对物(即生物粘附性物质)争夺被考虑的物质。这种分离将被给予的经过修饰的脂质体逆转形成规则的未经修饰的脂质体,从而使得给药经修饰的脂质体的给药目的失败。
为了形成被考虑的物质与脂质体的共价缀合物,已经研究了交联试剂用于有效性和生物相容性。一个这种试剂是戊二醛(GAD)。通过GAD交联的复合化学,建立了被考虑的物质的胺残基与脂质体之间的链接。
交联试剂可包括戊二醛(GAD)和水溶性的碳二亚胺,优选1-乙基-3-(3-二甲基氨基丙基)碳二亚胺(EDC)。被考虑的物质包括明胶、胶原和透明质酸(HA)。在这些方法之后,被考虑的物质可被用作附着剂或胶质以附着于脂质体,到达目标区域诸如肺上。
因此,尽管对于本发明是可有可无的,但是这种生物粘附性脂质体的使用,特别是那些具有透明质酸作为生物粘附性配体的脂质体的使用,将可能增加在肺部的渚留时间,减少粘膜纤毛清除和巨噬细胞摄取。
通常,在本发明制剂中优选使用环丙沙星,尽管可使用本领域技术人员已知的其它抗生素或抗感染药物。
根据本领域公知技术制备多层小泡(MLV)。简而言之,在一实施方案中,将脂质称重并溶解在适当的有机溶剂(诸如氯仿或氯仿-甲醇混合物)中。在旋转蒸发器中在低压下在约37-40℃的温度下将有机溶剂蒸发到全干。在蒸发后,将环丙沙星溶液加入到干脂质膜。有力地混合该系统,然后在例如振荡浴室中在适于脂质组合物的温度范围下温育约2小时。然后优选通过例如加入十分之一体积的10倍浓缩的pH 7.4的磷酸盐缓冲盐水(PBS)对该制备物进行缓冲。
在一实施方案中,如上所述产生的MLV用作酸性单层小泡(ULV)的源材料。例如,MLV如上所述进行制备并在诸如例如由Lipex Biomembranes Inc.(Vancouver,BritishColumbia)制造的装置中经历挤出过程。挤出通过一系列具有逐渐变小的孔径的膜进行,诸如,例如,从范围在0.8到1.0微米的孔径开始(每个孔径大小进行1到2次循环)并终止于根据所需脂质体大小所选择的孔径大小范围(例如,在最终的孔径大小下进行约7次挤出循环)。
示例性的脂质体组合物及其制造方法公开在美国专利6,890,555;6,855,296;6,770,291;6,759,057;6,623,671;6,534,018;;6,316,024;6,221,385和6,197,333中,所有这些专利并入本文作为参考。本发明的脂质体可以是多层、单层的,或诸如在上述专利中所述的任何已知的结构。本发明的脂质体优选由生物相容性脂质制造。通常,产生的脂质体的大小根据递送方式而异而具有宽范围,例如,对于肺递送,直径为1纳米到10微米或20纳米到1微米或约100纳米±20%。
II.包含环丙沙星的脂质体的药物制剂
在优选方案中,用脂质体包封的环丙沙星在气雾吸入装置中被给药到患者,但是可通过IV途径给予。在一些实施方案中,环丙沙星与也被包封的其它药物组合被包封在脂质体内。在一些实施方案中,环丙沙星与未包封的其它药物组合被包封在脂质体内。在一些实施方案中,脂质体与未包封的环丙沙星、与未包封的药物或其不同组合进行组合给药。
本发明的制剂可包括包含环丙沙星并结合一定量的有效增强脂质体穿过患者的肺表面并进入循环系统内的肺泡表面活性物质蛋白的脂质体。1991年4月9日授权的美国专利No.5,006,343(其作为参考并入本文)公开了脂质体和用于肺内递送的脂质体制剂。美国专利No.5,006,343中公开的制剂和方法可进行改编以应用环丙沙星并且可被包含在本发明的递送装置内从而提供了对囊性纤维化患者的有效治疗。
不管药物制剂的形式如何,优选制造用于吸入的小滴或粒子处在约0.5μm到12μm,优选1μm到6μm,更优选约2-4μm的范围内。通过制造具有相对较窄粒度范围的吸入粒子,有可能进一步增加药物递送系统的效率和改善剂量给药的再现性。因此,优选粒子不仅具有在0.5μm到12μm或2μm到6μm或约3-4μm范围内的粒度,而且平均粒度处在窄范围内以便被递送给患者的80%以上的粒子具有的粒子直径位于平均粒度的±20%内,优选位于平均粒度的±10%和更优选平均粒度的±5%内。
本发明的制剂可使用一次性包装和便携式的、手持式的、电池供电的装置诸如AERx装置被给药到患者(美国专利No.5,823,178,Aradigm,Hayward,CA)。作为替代,本发明的制剂可使用机械(非电子)装置进行。其它吸入装置可用于递送制剂,包括常规的喷射喷雾器,超声喷雾器,软雾吸入器,干粉吸入器(DPI),计量式剂量吸入器(MDIs),凝结气溶胶发生器和其它系统。
气雾剂可通过使药物强行通过具有孔大小在约0.25到6微米范围内的孔的膜来产生(美国专利5,823,178)。当孔具有这一大小时,脱离通过该孔而产生气雾剂的粒子的直径将为0.5到12微米。
药物粒子可随着试图保持处在这一粒度范围内的粒子的气流被释放。小粒子的产生可通过利用振动装置得以促进,所述振动装置提供了约800到约4000千赫的振动频率。本领域技术人员能够认识到,基于制剂的密度和粘度,可对诸如由其释放药物的孔的大小、振动频率、压力和其它参数的参数进行一些调整,切记一些实施方案的目的是提供具有直径在约0.5到12微米范围内的气雾化粒子。
脂质体制剂可以是低粘度液体制剂。药物自身或结合载体的粘度应当足够低以便该制剂可以被迫使脱离出孔以形成气雾剂,例如,使用20到200psi以形成优选具有的粒度为约0.5到12微米的气雾剂。
在一实施方案中,低沸点易挥发推进剂与本发明的脂质体和可药用赋形剂组合使用。脂质体可作为在推进剂中的悬浮液或干粉末形式被提供,或者,在另一个实施方案中,脂质体被溶解在位于推进剂内的溶液中。这两种制剂可被容易地容纳在具有阀作为其唯一开口的容器中。因为推进剂是易挥发的,即,具有低沸点,因此容器的内容物处在压力下。
根据另一个制剂,包含环丙沙星的脂质体作为单独的干粉剂形式被提供,并且根据又一个制剂,包含环丙沙星的脂质体作为溶液制剂形式被提供。干粉末可通过允许仅仅在用于每次递送的相同计量的吸气流速和吸气体积条件下被吸入被直接吸入。粉末可被溶解在水性溶剂中以产生溶液,该溶液穿过多孔膜以得到用于吸入的气雾剂。使得有可能制造可借助于肺内途径被吸入并递送给患者的包含环丙沙星的脂质体的气雾化形式的任何制剂可与本发明关联使用。关于可与气雾化递送装置关联使用的制剂的具体信息描述于Remington's Pharmaceutical Sciences,A.R.Gennaro编者(最新版本)Mack PublishingCompany中。关于胰岛素制剂,其也可用于关注Sciarra等人,(1976)的发现。当使用低沸点发射剂时,发射剂被保持在装置的加压罐内并保持为液体状态。当阀被启动时,推进剂被释放并强迫活性成分与推进剂一起从罐中被释放。推进剂当暴露于周围气氛下时将“消失”,即,推进剂立即蒸发。消失发生如此快使得实际上基本上纯的活性成分被递送到患者的肺。
III.剂量给药方案
基于以上所述,本领域技术人员可理解的是,可使用许多的不同的疗法和给药手段来治疗单个患者。因此,已经接受这种药物例如作为静脉内给药的环丙沙星或抗生素等等的患者可从本发明制剂的吸入中受益。一些患者可能只通过吸入接受包含环丙沙星的脂质体制剂。这些患者可能具有囊性纤维化症状,被确诊为罹患肺感染,或者具有医学状况的症状,这些症状可从对患者给药诸如环丙沙星的抗生素中受益。本发明的制剂还可用于诊断应用。在一实施方案中,例如,患者可接受一定剂量的本发明的作为诊断肺感染的程序的一部分,其中患者症状的一种或多种应答该制剂而有所改善。
患者典型地接受约0.01到10毫克/千克/天的剂量的环丙沙星±20%或±10%。这一剂量将典型地从气雾剂装置被给予至少一次“喷出”,优选若干次“喷出”。每天总剂量优选被每天给予至少一次,但是可被分成两个或更多个剂量进行每天给药。一些患者可从患者在数天或数周的时段内被给予更高剂量或更频繁给药的环丙沙星的“负荷”时段、然后给予降低剂量或维持剂量中受益。因为囊性纤维化典型地是慢性病况,因此预计患者接受这种治疗达延长时段。
先前在土拉热弗朗西斯氏菌(F.tularensis)的小鼠模型中已经表明吸入用脂质体包封的氟喹诺酮类抗生素可有效治疗肺感染并且还显示优于游离的或未包封的氟喹诺酮类(CA 2,215,716,CA 2,174,803和CA 2,101,241)。然而,他们并未预期将游离的氟喹诺酮类抗生素和被包封的氟喹诺酮类抗生素组合用于治疗那些肺感染的益处。根据本发明的一方面,高浓度的抗生素被立即递送同时还在数小时或一天内提供治疗剂的持续释放。
另一个申请EP1083881B1描述了包含药物-缀合物的脂质体,该药物-缀合物包括与氨基酸共价连接的喹诺酮化合物。该申请未预见需要既具有立即释放组分又具有持续释放组分来治疗那些肺感染。
另一个申请US 2000142026也描述了用脂质体包封的抗生素的使用。该申请讨论了给药更低剂量的用脂质体包封的抗生素的可能性,该更低剂量是游离的未包封抗生素的剂量的十分之一或百分之一。然而,他们未预期将游离抗生素和被包封的抗生素组合使用以提供在肺内的抗生素的最初的高治疗水平从而克服障碍以根除难以治疗的生物膜细菌。
因此,正如以上的讨论,根据本发明一些方面的制剂包括游离的或未包封的环丙沙星和用脂质体包封的环丙沙星的组合。这种制剂可由游离的环丙沙星产生立即益处导致抗生素浓度在肺内在细菌集落或生物膜周围迅速增加并降低细菌群体或生物膜的存活性,然后由被包封的环丙沙星产生持续益处,其继续杀死细菌或降低其复制能力,或降低抗生素耐药性集落产生的可能性。本领域技术人员可理解的是,本发明的制剂在治疗医学状况中的相对利益基于患者与患者之间的不同而异。
IV.其它制剂或载体
尽管脂质体已主要被描述为是为治疗剂提供包封并因此具有持续释放效应的媒介物,没有试图将制剂限制为是脂质体制剂。在肺内抗感染药物的立即释放和持续释放制剂或载体的组合可借助多种方式来实现,所述方式包括微球、聚合物、凝胶、乳液、粒子或悬浮液,其单独或组合使用。一些制剂或载体可具有导致与生物膜基质更密切结合的性质,并且这些性质关于增加抗感染药物在邻近生物膜细菌处的治疗水平方面证明是更加有利的。
各种受控释放制剂
持续释放聚合物制剂的实例是采用聚原酸酯作为媒介物。例如,参见美国专利No.4,304,767、4,957,998、5,968,543和WO 02/092661以及Adv.Polymer Sci.,107,41-92(1993)及其中的参考文献。这些受控释放聚合物的粘度据报道在1,500cP范围内(参见Biomaterials,23,2002,4397-4404)。对于更高分子量的聚合物需要相当高的力(参见Adv.Drug Del Reviews,53,2001,45-73)。
新型脂质体
各种长时间循环脂质体已经通过将糖脂或其它两性分子并入到常规脂质体的脂质双分子层中而制备。被截留在PEG化长时间循环脂质体内的加压素甚至在静脉注射后一个月仍保持生物活性(Woodle等人,1992)。
一个并非使用单层或多层脂质体的新手段是基于DEPOFOAM系统。这些多小泡脂质体(1-100微米)包含多个非同心的内部水性隔室并导致包封效率增加。在皮下注射后,被包封的肽和蛋白质的释放显示为,对于长效胰岛素为延长高达7天,对于制剂延长高达3周(Ye,Q等人,2000)。
Novosom AG公司已经获准了一种新型的用于蛋白质和肽的基于脂质体的储库系统的专利权。储库通过二步法制备:首先,将蛋白质溶解在水性介质中,然后将其加入到成膜物质的溶液中,这种成膜物质经过选择从而使得得到的膜参予与蛋白质的可逆的相互反应。这一温和条件的方法使得能够增加包封效率超过被并入蛋白的30%。另外,在皮下或肌肉注射储库后可获得一个月的持续的蛋白质释放(Panzner,S.,Novosom AG,申请No.2000-EP11079,WO 2001034115(2000))。这些研究已经证明了脂质体的基础适用性。脂质体的溶解性益处是公知的和已有报道的。
脂质纳米粒子和微球
固体脂质纳米粒子(SLN)代表了主要以甘油三酯为基础的胶态载体系统。由于SLN的疏水性及其小尺寸,SLN可能更适合结合亲脂性药物,所述亲脂性药物可容易地溶解在熔融的混合物中。例如,仅少量的溶菌酶可被并入到各种脂质中(Almeida等人,1997)。固体脂质纳米粒子拥有包封具有低溶解度药物(例如紫杉醇)的能力,用于药物寻靶中的表面修饰SLN的应用,或者可用作疫苗的佐剂。另外,可以假想SLN可以水分散体形式用于经口药物递送或者它们可替代地在常规剂型诸如片剂、胶囊或丸剂中用作添加剂。
美国专利No.6,277,413描述了具有基质的生物可降解的微球,所述基质包括至少一种类型的可生物降解的聚合物,和至少一种类型的脂质;和可从生物可降解的微球中释放的生理活性物质。
脂质晶体
EP 0767,656B1描述了一种药物组合物,其基于甘油-酯并包含二酰基甘油以及一种或多种磷脂,或者包括水、甘油、乙二醇或丙二醇在内的极性基团。组分之间的比例经过调整以形成L2相或液晶相,其中生物材料分散在或溶解在L2相或液晶相中。
油悬浮液
通常,油性介质的粘度比含水相诸如缓冲液的粘度显著更高。因此,通过采取油悬浮液可延长药物释放。另外,油性载体的粘度可进一步通过加入胶凝剂诸如单硬脂酸铝得以增加,从而使得能够控制工艺参数诸如药物溶解度和药物传送速度。使用油类作为药物载体的另一个重要的方面涉及化合物在油性介质内和组织周围的分配系数。具有高分配系数的亲脂性药物主要积聚在油性介质中,导致进一步降低有效药物起效的速度。
几年来,已将各种肽和蛋白质分散在油类中以制造持续释放制剂。Nestor等人早在1979年的专利涉及一种用于黄体生成素释放激素(LH-RH)的超兴奋剂类似物的长效的可注射储库制剂的开发,采用油类诸如花生油或芝麻油和胶凝剂诸如硬脂酸铝(Nestor等人,Syntex Inc.,美国专利No.4,256,737(1979))。
水凝胶
热致可逆的水凝胶在药物递送方面非常令人感兴趣。这些包括热敏胶凝材料,包括聚乙二醇/聚丙二醇嵌段共聚物(泊洛沙姆),聚乙二醇/聚丁二醇嵌段共聚物,泊洛沙姆-g-聚丙烯酸和N-异丙基丙烯酰胺的共聚物,其表现出在水性溶液中的溶胶-凝胶转化。聚氧化乙烯(PEG)和聚乳酸(PLA)的二嵌段共聚物,PEG-PLGA-PEG三嵌段共聚物也被用作可替代的水凝胶,其在生理学条件下将提供生物可降解的和可注射的药物递送系统。一些天然聚合物,包括明胶、琼脂糖、淀粉酶、支链淀粉、纤维素衍生物、角叉菜胶和节冷胶,表现出热致可逆的胶凝行为。天然聚合物的一些纤维素衍生物,诸如甲基纤维素和羟基丙基纤维素,表现出反向热胶凝行为(在高温下胶凝)。这些水凝胶的粘度是非肠道递送时所关心的问题。这些水凝胶的粘度在低剪切速率下可以极高(Thorgeirsdottir TO等人,2005)。聚羟基甲基丙烯酸酯被广泛用在水凝胶制剂中(Peppas等人,2000)。美国专利No.6,602,952描述了聚合物结构,其包括多功官能聚烯化氧诸如聚乙二醇衍生物,其与选自以下的聚合物共价交联:脱乙酰壳多糖和脱乙酰壳多糖的缀合物和单官能聚烯化氧诸如甲氧基聚乙二醇。在水性介质中,聚合物结构形成水凝胶。
储库制剂
可植入的药物递送装置为治疗许多疾病和病况提供了一种吸引人的治疗工具,特别是当将持续释放效应附加到治疗中时。已经开发了各种可植入的药物递送装置,并且基于不同的机制而实现了药物从储库向治疗部位的移动。美国专利No.4,938,763公开了形成原地植入物的方法,通过将非反应性的水不溶性热塑性聚合物溶解在生物相容性的水溶性溶剂中形成液体,将该液体置于体内,并允许溶剂消散以得到固体移植物。美国专利No.5,747,058描述了用于物质的受控释放的组合物,该物质包括在体温下粘度为至少5,000cP的非聚合物型、非水溶性、高粘度的液体载体材料,其在周围或生理学条件下不整齐结晶。
大分子的递送
蛋白或肽药物被附加到抗感染药物制剂中可提供附加的治疗益处。前面论述的实施例包括百慕时(Pulmozyme)重组人脱氧核糖核酸酶,其被批准用于治疗CF。尽管一些大分子可在低剂量下或在相对低浓度下被递送,但是对于其它的大分子说来在高浓度下递送是必需的。在高浓度下的蛋白质制剂可具有的物理性质冲击了容易递送蛋白质药物的能力。美国专利No.6,541,606描述了被包封在包括聚合物的载体基质内的蛋白质晶体或晶体制剂以形成组合物。该制剂和组合物增强了蛋白质的天然的生物学活性三级结构的保持性并产生了储库,当需要时该储库可在所需部位缓慢释放活性蛋白质。
缀合系统
聚合物载体系统可在避免被巨噬细胞摄取方面具有某些优于非聚合物载体的优点。因为脂质体是由磷脂形成的球形小泡粒子,它们可被巨噬细胞吞噬。可在肝和脾中发现高水平,即使当脂质体通过用PEG进行包衣而具有“隐形(stealth)”特征时。同时,抗体具有的缺点是肿瘤细胞上的大多数受体也存在于正常细胞上,使得很难发现只有癌才有的那些。
相比之下,水溶性聚合物允许与单个分子而不是较大粒子协作。为了避开肝和脾,可以使用不带电的亲水性聚合物诸如PEG和N-(2-羟丙基)甲基丙烯酰胺。当这些聚合物发生水合时,它们可在血液中循环长达约24小时的时段((C&E News,第80卷,第34期,39-47)。
其它缀合系统的实例包括PEG化。PEG化通过增加分子的表观分子量而降低从血流的清除速率。直到某一大小,蛋白质的肾小球滤过速率与蛋白质的尺寸成反比。降低的清除速率可导致优于非PEG化材料的效率增加(Conforti等人,1987和Katre等人,1987)。缀合可以在体外或者体内进行。
WO2005034909A2描述了与核心连接的高支化聚合物和生物学活性部分。生物学活性部分依靠不可酶促裂解的连接器L连接于核心上。该组合物可被用于递送生物学活性部分到其靶标上。
美国专利No.6,946,134描述了与白蛋白或白蛋白的片段或变体融合的治疗性蛋白,其表现出延长的贮藏期限和/或延长的或在溶液中的治疗活性。白蛋白作为载体分子的作用及其惰性性质对于作为体内多肽的载体和转运蛋白是希望的性质。白蛋白作为白蛋白融合蛋白的一个组分被用作各种蛋白质的载体已在WO93/15199、WO93/15200和EP413622中被建议。还建议了用于与多肽融合的HA的N末端片段的使用(EP399666)。
美国专利No.5,367,051描述了富勒烯官能化的含胺聚合物和可聚合物的单体,特征在于在聚合形式下具有高温稳定性,即,能够经得起至少约300℃的温度。富勒烯基团通过聚合物上的胺基被键合到聚合物上。
WO专利No.2005073383描述了新型的杂二聚融合蛋白,其包括第一多肽和第二多肽,其中第一多肽包括FSH(aFSH)的α亚单位,其直接或间接地与新生Fc受体(FcRn)的结合配对物连接,第二多肽包括FSH(βFSH)的β亚单位,其直接或间接地与FcRn结合配对物连接。缀合的多肽与常规形式的FSH治疗相比具有增加的半衰期和生物利用度。
树枝型聚合物
树枝型聚合物是轮廊分明的聚合物结构。树枝型聚合物基于从中心核心发源的重复的高支化结构(US 4,507,466)。典型的树枝型聚合物基于聚酰胺基胺(PAMAM)、聚乙烯亚胺(PEI)、聚丙烯亚胺或聚赖氨酸。这些合成大分子以逐步方式进行装配,每个反应周期增加另一个分支层(称作“代”)。树枝型聚合物通过逐步的、分叉的“从底到顶”或收敛的“从顶到底”的合成方式获得。中心结构组分是核心单元,高支化树枝型聚合物从该单元以放射状的对称方式进行延长。核心可提供至少两个反应性基团用于树枝型聚合物的缀合,其还可具有杂官能性质并且可使用保护基。在后一种情况中,树枝型聚合物可进行装配,并且客体化合物可随后借助直角化学被缀合到苯胺核心上(WO88/01180)。核心和树枝型聚合物形成树枝型聚合物的内部或骨架。作为由空间群集所支撑的球形对称的结果,高支化的末端基团被称作外部。在更高代的树枝型聚合物中,已经发现末端分支形成相当稠密的壳和挠性的内部空隙。可理解的是,对于给定的树枝型聚合物,这些空穴被向后折叠的端基和紧密配位的溶剂分子所充满。树枝型聚合物与胶束有关,同样地非常适合于复杂的疏水性化合物。但是相比之下,它们表现出更高的结构等级,因为它们的单分子性质和缺乏各种物质的动态平衡,如果满足某些结构要求,诸如构造刚性和扁平性以及电荷分布诸如对叔胺的亲合性,合成化合物只能分散形成树枝型聚合物。各种非极性化合物诸如嵌二萘或萘已被包封在树枝型聚合物中。
在美国专利No.5,714,166和WO95/24221中,已经揭示了树枝型聚合物-蛋白质缀合物。G4的PAMAM树枝型聚合物通过其末端官能团共价结合于胰岛素、荧光标记胰岛素、抗生物素蛋白、单克隆抗体和血管舒缓激肽。用于缀合的反应性基团仅仅存在于树枝型聚合物的表面上,并因此通过浸出方法产生的任何共价加合物将结合于树枝型聚合物外部。
PAMAM树枝型聚合物在其表面上包含游离的胺基并容易通过库伦相互作用与DNA结合。
WO01/07469详细描述了包括鸟氨酸和甘氨酸氨基酸的水溶性多肽树枝型聚合物。该专利申请还教导了在温和条件下在肝素的存在下通过树枝型聚合物核心的分支化而进行低聚糖、肝素的非共价包封。低聚糖通过树枝型聚合物骨架内的W-不稳定键的光诱导裂解而从树枝型聚合物中释放。其中使用的核心结构是三(2-马来酰胺基乙基)胺。
其它聚合物系统
在开发避免被噬菌作用早期俘获的药物载体的过程中,在模拟生物手段中评价了肝素、右旋糖酐和甲基丙烯酸甲酯的使用(Passirani等人,1998)。
聚磷腈和聚苯乙烯的杂化嵌段共聚物和接枝共聚物的合成是将两种聚合物的属性组合以产生新性质的一种方法。磷腈和苯乙烯均聚物各自的许多有价值的性质可被组合而不损失聚苯乙烯和聚磷腈聚合物二者的总体的固态或溶液性质。美国专利No.6,392,008描述了这种包含聚磷腈聚合物的组合物。
美国专利No.5,176,907描述了生物相容性和生物可降解的聚磷酸酯-氨基甲酸酯,包括该聚磷酸酯-氨基甲酸酯的组合物,和使用其作为药物递送装置和移植物的方法。
V.联合治疗
本发明的脂质体制剂可同时地与本文所述的其它药物被给予。例如,本发明的脂质体可与诸如以下的药物一起使用:脱氧核糖核酸酶,粘液溶解剂,上调氯离子通道或增加穿过细胞上皮表面的离子流的化学品,支气管扩张药,甾族化合物,P2Y2激动剂,弹性酶抑制剂诸如α-1抗胰蛋白酶(AAT),N-乙酰半胱氨酸,增强抗生素对抗生物膜细菌的活性的药剂诸如水杨酸钠,干扰素γ,干扰素α,或选自以下的氟喹诺酮类:氨氟沙星、西诺沙星、环丙沙星、达氟沙星、二氟沙星、依诺沙星、恩诺沙星、氟罗沙星、伊洛沙星、诺美沙星、米洛沙星、诺氟沙星、氧氟沙星、培氟沙星、罗索沙星、芦氟沙星、沙拉沙星、司帕沙星、替马沙星和妥舒沙星,或选自以下的抗生素:妥布霉素、多粘菌素E、阿奇霉素、阿米卡星、头孢克洛(希刻劳)、氨曲南、阿莫西林、头孢他啶、头孢氨苄(Keflex)、庆大霉素、万古霉素、亚胺培南、多利培南、哌拉西林、米诺环素或红霉素。
前述仅仅说明本发明的原则。可以理解的是,本领域技术人员能够设计各种布置,尽管这些布置未在本文中被明确地描述或说明,但是这些布置体现了本发明的原则,并且被包含在本发明的精神和范围内。另外,本文所述的全部的实施例和条件性语言主要意在帮助读者了解本发明的原则和由本发明人所贡献的观念以推动本领域的发展,并且不被认为将本发明限制到这些被明确描述的实施例和条件。另外,本文的叙述了本发明的原则、方面和实施方案及其具体实施例的全部声明意在包含其结构和功能等价物。另外,这种等价物意在包括目前已知的等价物和将来被开发的等价物,即,任何执行相同的功能而不论结构如何的任何被开发的要素。因此,本发明的范围不意在受限于本文说明和描述的示例性的实施方案中,而是,本发明的范围和精神由权利要求书来体现。
VI.治疗方法
直到目前为止,我们已经主要讨论了本发明在治疗囊性纤维化患者的感染中的应用。然而,本领域技术人员显然可理解本发明可用于超出CF之外的应用和优点。这种治疗方法适用于其它的牵涉鼻通道、气道、内耳或肺的感染的疾病状况,其包括但不限于:支气管扩张、肺结核、肺炎;包括但不限于:呼吸机相关性肺炎,社区获得性肺炎,支气管性肺炎,大叶性肺炎;由肺炎链球菌、衣原体、肺炎支原体、葡萄球菌引起的感染,预防性治疗或预防其中感染可能出现的病况,例如插管或呼吸患者,肺移植患者中的感染,支气管炎,百日咳,内耳感染,链球菌性疫喉,吸入性炭疽,土拉菌病或窦炎。
具体实施方式
提出以下实施例以便为本领域普通技术人员提供完整的关于如何实施和使用本发明的公开和说明,并且不意在限制本发明人所认为的发明范围,也不意在代表以下的试验是唯一进行的试验。已经进行了努力以确保关于所用数字(例如量、温度等)的准确性,但是应当考虑存在一些实验误差和偏差。除非另外说明,否则份数是指重量份数,分子量是指重量平均分子量,温度是指摄氏度,压力是指大气压力或接近大气压力。
实施例1
被包封的环丙沙星的制造:
环丙沙星(50mg/mL)被包封在脂质体中,该脂质体组成如下:氢化大豆磷脂酰基-胆碱(HSPC)(70.6mg/mL)、天然大豆磷脂酰胆碱的半合成的全氢化衍生物(SPC)和胆固醇(29.4mg/mL)。脂质为双分子层结构,平均粒度为75到120nm。将无菌悬浮液悬浮在等渗缓冲液(25mM组氨酸,145mM NaCl,pH 6.0,300mOsm/kg)中并通过吸入给药。这些脂质体环丙沙星制剂包含约1%的未包封的环丙沙星。
制造过程包括以下步骤。
1.缓冲液的制备。
2.脂质组分的称重。
3.脂质在溶剂中的增溶(tBuOH:EtOH:dH2O/49:49:2).
4.将脂质在溶剂中的溶液与硫酸甲胺缓冲液(10%v/v溶剂)混合以形成多层小泡(MLV),其含有在30mg/mL脂质浓度下的被包封的硫酸甲胺。
5.挤出通过四个堆叠的80纳米孔大小的聚碳酸酯过滤器以产生大单层小泡(LUV)。进行第二次挤出通过以产生平均直径为~100纳米的脂质体。
6.超滤以将脂质体浓缩到~55mg/mL总脂质。
7.相对于10体积的缓冲液(145mM NaCl,5mM组氨酸,pH 6.0)进行渗滤,以除去乙醇并产生跨膜pH梯度。
8.通过HPLC测定脂质浓度。
9.将脂质体悬浮液加热到50℃并缓慢加入环丙沙星粉末(总脂质质量的60%)并同时搅拌。逐渐加入环丙沙星(每4分钟加入质量的10%,在40分钟内进行)并且将产物在50℃温育20分钟,然后加入最后一小份以完成药物装载过程。
10.相对于3体积的145mM NaCl,5mM乙酸盐,pH 4.0进行装载有环丙沙星的脂质体的渗滤以除去未包封的环丙沙星,在其中游离环丙沙星是可溶的条件下进行。
11.相对于5体积的145mM NaCl,25mM组氨酸,pH 6.0进行装载有环丙沙星的脂质体的渗滤以除去任何残留的未包封的环丙沙星,进一步降低残留溶剂的水平并进行外部缓冲液的交换用于所需的最终产物缓冲液。
12.将制剂超滤达到环丙沙星浓度为50mg/mL(生产中的检验要求)。
13.将脂质体预先过滤通过0.45/0.2微米的滤板以除去可阻塞灭菌级过滤器的粒子。使用的过滤器实际上是灭菌级过滤器;然而,它们在高压下被使用而不与它们的无菌过滤作用相矛盾。
14.在此过滤通过0.2微米的灭菌级过滤器。
15.样品的装瓶和包装。
总的制造方案如图1所示。
感染模型的说明:
在铜绿假单胞菌肺感染的小鼠模型中评价了包封环丙沙星的脂质体。在用装载有铜绿假单胞菌的琼脂糖小珠感染后,经内脏校正的Cftr剃除小鼠已经显示具有囊性纤维化肺表型(van Heeckeren等人,2004),并且与UNC Cftr剃除小鼠具有相似的炎性应答(vanHeeckeren等人,2004)。所有这些特征使得其成为被选品系用于研究药物在囊性纤维化肺感染小鼠模型中是否具有效力,如果没有效力是否在野生型小鼠和囊性纤维化小鼠之间具有差别性应答。一种性别即雄性小鼠用于消除性别带来的可能的混淆。所有小鼠为6-8周龄并且重量大于16克。
装载有铜绿假单胞菌的琼脂糖(PA)小珠如前所述被制造和使用(van Heeckeren等人,1997,van Heeckeren等人,2000,van Heeckeren和Schluchter,2002),具有微小差异。对小鼠灌注小珠的1:35的稀释物,并且小珠被递送进入用异氟烷麻醉的小鼠中。将其确立为是LD50剂量,尽管由于实验与实验之间的细微差别可导致不可预测的差别性应答。也就是说,在一个实验中,所述剂量是LD50,但是在另一个实验中,所述剂量可以是LD90。因为本发明人所关心的是研究这些药物是否具有临床效力,本发明人试图获得在被感染的CF对照小鼠中的LD50和LD90范围之间的剂量。如果小鼠濒临死亡(正位反射严重延迟和可触知的变冷)则进行干预性安乐死,并且进行尸体解剖以确定是否有明显的肺感染。被处死的小鼠与已发生自发性死亡的小鼠一样被包含在内。
脂质体环丙沙星治疗:
脂质体环丙沙星制剂或赝品(稀释剂)(≤0.05ml)经鼻内递送。
剂量-范围探索研究的设计:
实验了三个剂量:由99%的被包封的环丙沙星和1%的游离环丙沙星组成的全部浓度(50mg/ml)环丙沙星的10%、33%和100%,加上脂质体稀释剂作为阴性对照。通过稀释制备了低剂量和中剂量。在第0天,对小鼠经气管接种装载有铜绿假单胞菌的琼脂糖小珠,其在无菌PBSpH 7.4中以1:35稀释。在第2-9天,小鼠每天一次用药物或稀释剂赝品治疗。在第10天,将小鼠处死,测量结果包括临床征象(包括表皮质量、姿势、将其置于侧卧姿势后自身变成正卧的能力,走动),最初体重的改变,和存活。在处死时,注意到了大体肺病理,使用1ml无菌PBS pH7.4进行支气管肺泡灌洗(BAL),检验了全血、未处理的BAL液和脾匀浆中是否存在铜绿假单胞菌,并且使用血球计进行BAL细胞的计数。
存活结果:
图2显示了每组存活超过10天的累积存活率,作为存活小鼠数的百分数被报道。在第10天,用脂质体环丙沙星治疗的三个组比稀释剂对照组具有更高的存活率。在每个用脂质体治疗的组中仅有2例死亡,而在稀释剂组中有6例死亡。在所有组中100%剂量组具有最长存活,所有小鼠存活超过5天,而其它组全都在第5天时有2例死亡。
鼻内给药(以靶向于肺)用脂质体包封的环丙沙星(其包含约1%的游离的环丙沙星)增加了罹患铜绿假单胞菌肺感染的小鼠的存活率。因此,吸入式脂质体环丙沙星在囊性纤维化患者中是有效的,或者在具有肺感染的其它疾病中是有效的。
图2表示在感染后的累积存活率。在第0天用装载有铜绿假单胞菌的琼脂糖感染小鼠。小鼠从第2天开始到第9天结束,每天使用三种不同浓度(100%,空心菱形;33%实心正方形;或10%,空心三角形)之一的环丙沙星(药物)的脂质体制剂进行鼻内治疗。稀释剂用作对照(实心圈)。在第10天处死存活的小鼠。
实施例2
未包封的环丙沙星的制备:制备了浓度为30mg/mL的未包封的或“游离”的环丙沙星在10mM乙酸钠pH 3.2中的溶液。
被包封环丙沙星的制造:如实施例1所述,将环丙沙星(50mg/mL)包封在脂质体中,该脂质体组成如下:氢化大豆磷脂酰基-胆碱(HSPC)(70.6mg/mL)、天然大豆磷脂酰胆碱的半合成的全氢化衍生物(SPC)和胆固醇(29.4mg/mL)。该脂质体制剂的表征表明有约1%的环丙沙星是游离的;也就是说,其未被包封在脂质体内。
感染模型的说明:如实施例1所述,在另外两个实验中在铜绿假单胞菌肺感染小鼠模型中评价了包含游离的环丙沙星和用脂质体包封的环丙沙星的制剂。
剂量-范围探索研究的设计:在两个单独实验中评价了一个剂量的游离环丙沙星和脂质体环丙沙星的组合(0.36mg/kg游离环丙沙星和0.6mg/kg脂质体环丙沙星),两个剂量的脂质体环丙沙星(0.6mg/kg和1.2mg/kg)和作为阴性对照的脂质体稀释剂。在第0天,对小鼠经气管接种装载有铜绿假单胞菌的琼脂糖小珠,其在无菌PBS pH 7.4中以1:35稀释。在第2-9天,小鼠每天一次用药物或稀释剂赝品处理。在第0天,将小鼠处死。测量结果包括临床征象(包括表皮质量、姿势、将其置于侧卧后自身变成正卧的能力,走动),最初体重的改变,和存活。在处死时,注意到了大体肺病理,使用1ml无菌PBS pH 7.4进行支气管肺泡灌洗(BAL),检验了全血、未处理的BAL液和脾匀浆中是否存在铜绿假单胞菌,并且使用血球计进行BAL细胞的计数。
存活结果:表1显示了每组在超过10天后的累积存活率,作为得自两个研究的存活小鼠数的百分数被报道。在第10天,用游离环丙沙星和脂质体环丙沙星的组合治疗的所有组比稀释剂对照组具有更高的存活率。
表1:得自在铜绿假单胞菌肺感染CF小鼠中进行的两个研究中的每组平均存活率,采用鼻内滴注ARD-3100或对照进行治疗。
结论:鼻内给药(以靶向于肺)用脂质体包封的环丙沙星增加了罹患铜绿假单胞菌肺感染的小鼠的存活率。被吸入的脂质体环丙沙星、或游离环丙沙星和脂质体环丙沙星的组合在囊性纤维化患者中是有效的,或者在具有肺感染的其它疾病中是有效的。
实施例3
被包封的环丙沙星的制造:如实施例1所述,将环丙沙星(50mg/mL)包封在脂质体中,该脂质体组成如下:氢化大豆磷脂酰基-胆碱(HSPC)(70.6mg/mL)、天然大豆磷脂酰胆碱的半合成的全氢化衍生物(SPC)和胆固醇(29.4mg/mL)。该脂质体制剂的表征表明有约1%的环丙沙星是游离的;也就是说,其未被包封在脂质体内。
游离环丙沙星和被包封的环丙沙星的组合的递送:不使用既包含游离环丙沙星又包含被包封的环丙沙星的制剂,而是采用替代方法在递送事件期间来制造混合物。例如,以受控方式附加剪切力或热可重现地产生一些丧失其完整性并释放先前被包封在脂质体内的药物内容物的脂质体。使用电动机械AERx系统的研究证实了使用这一手段的可能性。使用AERx系统递送包含约99%被包封的环丙沙星的制剂并且收集气雾剂小滴。使用设定在13、45、77、108和140℃温度下的温度控制器,被收集的气雾剂分别包含89、84、82、77和41%的被包封药物。
本发明在被认为是最现实的和优选方案的意义上进行了说明和描述。然而,可承认的是,从本发明的偏离也处在本发明的范围内并且可由本领域技术人员在阅读了本公开后可进行明显修改。
尽管本发明已经参考其具体实施方案进行了描述,但是本领域技术人员可理解的是可进行各种改变并且可用等价物进行替换而不脱离本发明的真实精神和范围。另外,可进行许多修改以使特定的位置、材料、物质组成、方法、一个或多个工艺步骤适合于本发明的目的、精神和范围。所有这些修改意在被包含在权利要求书的范围内。
参考文献
以下每篇参考文献作为参考并入本文。
Almeida JA,Runge S,Mülleret RH,Peptide-loaded solid lipidnanoparticles(SLN):Influence of production parameters.Int J Pharm.149(2)(1997)255-265。
Bangham AD,Standish MM,Watkins JC,Diffusion of univalent ions acrossthe lamellae of swollen phospholipids.J Mol Biol.13(1)(1965)238-252。
Conforti A,Franco L,Milanino R,Velo GP,Boccu E,Largajolli E,SchiavonO,Veronese FM.PEG superoxide dismutase derivatives:anti-inflammatory activityin carrageenan pleurisy in rats.Pharm Research Commun.19,pg.287,1987。
Costerton JW,Lewandowski Z,Caldwell DE,Korber DR,Lappin-Scott HM.,Microbial biofilms.Annu Rev Microbiol.1995;49:711-45。
Fitzsimmons SC.The changing epidemiology of cystic fibrosis.JPediatr.1993Jan;122(1):1-9。
Gilbert P,Das J,Foley I.,Biofilm susceptibility to antimicrobials.AdvDent Res.1997Apr;11(1):160-7。
Helle J,Barr J,Ng SY,Shen HR,Schwach-Abdellaoui K,Gurny R,Vivien-Castioni N,Loup PJ,Baehni P,Mombelli A.Development and applications ofinjectable poly(ortho esters)for pain control and periodontaltreatment.Biomaterials,23,2002,4397-4404。
Hodson M,Shah PL,DNase trials in cystic fibrosis.Respiration 1995;62,Suppl 1:29-32。
Katre NV,Knauf MJ,Laird WJ.,Chemical modification of recombinantinterleukin 2by polyethylene glycol increases its potency in the murine MethA sarcoma model.Proc Natl Acad Sci.U.S.A.vol.84,1487-91,1987。
LiPuma JJ.,Microbiological and immunologic considerations withaerosolized drug delivery.Chest.2001Sep;120(3Suppl):118S-123S。
Lode H,Borner K,Koeppe P,Schaberg T.,Azithromycin--review of keychemical,pharmacokinetic and microbiological features.J AntimicrobChemother.1996;37,Suppl C:1-8。
Moss RB.,Administration of aerosolized antibiotics in cystic fibrosispatients.Chest.2001 Sep;120(3 Suppl):107S-113S。
Passirani C,Barratt G,Devissaguet JP,Labarre D.,Long-circulatingnanoparticles bearing heparin or dextran covalently bound to poly(methylmethacrylate).Pharm Res.1998 Jul;15(7):1046-50。
Peppas Bures P,Leobandung W,Ichikawa H.,Hydrogels in pharmaceuticalformulations.Eur J of Pharm and Biopharm.2000 Jul;50(1):27-46.Review。
Polonio RE Mermel LA,Paquette GE,Sperry JF.,Eradication of biofilm-forming Staphylococcus epidermidis(RP62A)by a combination of sodiumsalicylate and vancomycin.Antimicrob Agents Chemother.2001 Nov;45(11):3262-6。
Schroeder SA Gaughan DM,Swift M.,Protection against bronchial asthmaby CFTR delta F508 mutation:a heterozygote advantage in cystic fibrosis.NatMed.1995 Jul;1(7):703-5。
Sciarra JJ,Patel SP.,In vitro release of therapeutically activeingredients from polymer matrixes.J of Pharm Sci.1976 Oct;65(10):1519-22。
Smith AL,Ramsey BW,Hedges DL,Hack B,Williams-Warren J,Weber A,GoreEJ,Redding GJ.Safety of aerosol tobramycin administration for 3 months topatients with cystic fibrosis.Ped Pulmonol.1989;7(4):265-271。
Thorgeirsdottir TO,Kjoniksen AL,Knudsen KD,Kristmundsdottir T,NystromB.Viscoelastic and Structural Properties of Pharmaceutical HydrogelsContaining Monocaprin.Eur.J.of Pharm.and Biopharm.2005 Feb;59(2):333-42。
Van Heeckeren AM,Schluchter MD,Drumm ML,Davis PB.Role of Cftrgenotype in the response to chronic Pseudomonas aeruginosa lung infection inmice.Am J Physiol Lung Cell Mol Physiol.2004 Nov;287(5):L944-52.Epub 2004 Jul9。
Van Heeckeren AM,Scaria A,Schluchter MD,Ferkol TW,Wadsworth S,DavisPB.Delivery of CFTR by adenoviral vector to cystic fibrosis mouse lung in amodel of chronic Pseudomonas aeruginosa lung infection.Am J Physiol Lung CellMol Physiol.2004 Apr;286(4):L717-26.Epub 2003 Sep 26。
Van Heeckeren A,Ferkol T,Tosi M.,Effects of bronchopulmonaryinflammation induced by pseudomonas aeruginosa on adenovirus-mediated genetransfer to airway epithelial cells in mice.Gene Ther.1998 Mar;5(3):345-51。
Van Heeckeren AM,Schluchter MD.,Murine models of chronic Pseudomonasaeruginosa lung infection.Lab Anim.2002 Jul;36(3):291-312。
Van Heeckeren AM,Tscheikuna J,Walenga RW,Konstan MW,Davis PB,ErokwuB,Haxhiu MA,Ferkol TW.Effect of Pseudomonas infection on weight loss,lungmechanics,and cytokines in mice.Am J Respir Crit Care Med.2000 Jan;161(1):271-9。
Weber A,Smith A,Williams-Warren J,Ramsey B,Covert DS.,Nebulizerdelivery of tobramycin to the lower respiratory tract.Pediatr Pulmonol.1994May;17(5):331-9。
Wolter J,Seeney S,Bell S,Bowler S,Masel P,McCormack J.,Effect of longterm treatment with azithromycin on disease parameters in cystic fibrosis:arandomised trial.Thorax 2002;57:212-216。
Woodle MC,Storm G,Newman MS,Jekot JJ,Collins LR,Martin FJ,Szoka FCJr.,Prolonged systemic delivery of peptide drugs by long-circulatingliposomes:illustration with vasopressin in the Brattleboro rat.Pharm Res.1992Feb;9(2):260-5。
Zielenski J,Tsui LC.,Cystic fibrosis:genotypic and phenotypicvariations.Annual Rev Genet.1995;29:777-807。
Ye,Q,Asherman J,Stevenson M,Brownson E,Katre NV.,DepoFoam technology:a vehicle for controlled delivery of protein and peptide drugs.J ControlRel.Feb 14;64(1-3):155-66。
Claims (7)
1.用于治疗感染的粒子的气雾化组合物,其包括:
游离的未包封的环丙沙星,其量占总的游离的环丙沙星和用脂质体包封的环丙沙星的1%到75%;
可药用的赋形剂;和
用脂质体包封的环丙沙星,其中所述脂质体组成如下:50mg/mL的环丙沙星、70.6mg/mL的氢化大豆磷脂酰基-胆碱和29.4mg/mL的胆固醇,其中所述脂质体的脂质为包封环丙沙星的双分子层结构,得到平均粒度为75nm到120nm的脂质体,以及其中所述脂质体被悬浮在由25mM组氨酸和145mM NaCl组成的pH 6.0以及300mOsm/kg的等渗缓冲液中;
其中该组合物被配制用于气雾化递送。
2.权利要求1的气雾化组合物,其中用脂质体包封的环丙沙星以每小时0.1到100%的速率被释放,在1到24小时后发生抗生素的接近完全的释放。
3.权利要求1的气雾化组合物,其中用脂质体包封的环丙沙星以每小时0.5到20%速率被释放,在1到24小时后发生抗生素的接近完全的释放。
4.权利要求1的气雾化组合物,其中用脂质体包封的环丙沙星以每小时2到10%的速率被释放,在1到24小时后发生抗生素的接近完全的释放。
5.权利要求1的气雾化组合物,其还包含选自支气管扩张药和抗炎药的附加的药学活性药物。
6.权利要求5的气雾化组合物,其中支气管扩张药选自β-肾上腺素能受体激动剂、抗毒蕈碱药物及其组合。
7.权利要求5的气雾化组合物,其中抗炎药选自皮质甾类、白细胞三烯受体拮抗体、白细胞三烯合成抑制剂和环加氧酶抑制剂。
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Families Citing this family (47)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7718189B2 (en) * | 2002-10-29 | 2010-05-18 | Transave, Inc. | Sustained release of antiinfectives |
CA2838111C (en) | 2005-12-08 | 2016-01-19 | Insmed Incorporated | Lipid-based compositions of antiinfectives for treating pulmonary infections and methods of use thereof |
ES2668554T3 (es) * | 2006-04-06 | 2018-05-18 | Insmed Incorporated | Métodos para la encapsulación liposomal inducida por coacervación y sus formulaciones |
US8268347B1 (en) * | 2006-10-24 | 2012-09-18 | Aradigm Corporation | Dual action, inhaled formulations providing both an immediate and sustained release profile |
US8119156B2 (en) * | 2006-10-24 | 2012-02-21 | Aradigm Corporation | Dual action, inhaled formulations providing both an immediate and sustained release profile |
US20100196455A1 (en) * | 2007-05-04 | 2010-08-05 | Transave, Inc. | Compositions of Multicationic Drugs for Reducing Interactions with Polyanionic Biomolecules and Methods of Use Thereof |
US9333214B2 (en) | 2007-05-07 | 2016-05-10 | Insmed Incorporated | Method for treating pulmonary disorders with liposomal amikacin formulations |
US9119783B2 (en) | 2007-05-07 | 2015-09-01 | Insmed Incorporated | Method of treating pulmonary disorders with liposomal amikacin formulations |
US9114081B2 (en) | 2007-05-07 | 2015-08-25 | Insmed Incorporated | Methods of treating pulmonary disorders with liposomal amikacin formulations |
US20110105995A1 (en) * | 2008-01-16 | 2011-05-05 | Zhu Ting F | Uniform-sized, multi-drug carrying, and photosensitive liposomes for advanced drug delivery |
TW201010708A (en) * | 2008-06-02 | 2010-03-16 | Intervet Int Bv | Composition comprising an antibiotic and a corticosteroid |
CN102231978B (zh) * | 2008-10-07 | 2016-01-20 | 耶路撒冷希伯来大学伊森姆研究发展公司 | 包含包埋在聚合物基质中的脂质体的组合物和其使用方法 |
CA2784033A1 (en) * | 2009-12-22 | 2011-07-21 | Kalobios Pharmaceuticals, Inc. | A method of treating a staphylococcus infection in a patient having a low-level pathogenic pseudomonas aeruginosa infection |
SG10202010355PA (en) | 2010-03-12 | 2020-11-27 | Berg Llc | Intravenous formulations of coenzyme q10 (coq10) and methods of use thereof |
CN102309448B (zh) * | 2010-06-29 | 2014-07-09 | 中国人民解放军军事医学科学院毒物药物研究所 | 一种肺部给药的环丙沙星药用组合物及其制备方法 |
ES2770575T3 (es) | 2010-10-28 | 2020-07-02 | Pacira Pharmaceuticals Inc | Formulación de liberación sostenida de un fármaco antiinflamatorio no esteroideo |
IT1405998B1 (it) * | 2010-12-09 | 2014-02-06 | Bionest Ltd | Gel polifunzionale contro la secchezza vaginale ad effetto diretto e ritardato |
EP2720680B1 (en) * | 2011-06-17 | 2020-02-12 | Berg LLC | Inhalable pharmaceutical compositions |
WO2013057208A1 (en) * | 2011-10-18 | 2013-04-25 | Targeted Delivery Technologies Limited | Compositions and methods for reducing the proliferation and viability of microbial agents |
JP6285865B2 (ja) | 2011-11-14 | 2018-02-28 | アルファシグマ ソシエタ ペル アチオニ | うつ病を有する対象のための処置レジメンを選択するためのアッセイ及び方法 |
CN108743537B (zh) | 2012-05-21 | 2021-06-11 | 英斯麦德公司 | 治疗肺部感染的系统 |
WO2014058974A1 (en) * | 2012-10-10 | 2014-04-17 | Emory University | Methods of managing inflammation using glycolysis pathway inhibitors |
CN104884047A (zh) | 2012-11-29 | 2015-09-02 | 英斯梅德股份有限公司 | 稳定的万古霉素制剂 |
EP3060198A4 (en) | 2013-10-22 | 2017-06-28 | Aradigm Corporation | Inhaled surfactant-modified liposomal formulations providing both an immediate and sustained release profile |
WO2015136446A1 (en) | 2014-03-11 | 2015-09-17 | Nestec S.A. | Methods for selecting antidepressant drug therapy to treat depression |
CA2943049A1 (en) | 2014-04-08 | 2015-10-15 | Aradigm Corporation | Liposomal ciprofloxacin formulations with activity against non-tuberculous mycobacteria |
RU2016143591A (ru) | 2014-04-08 | 2018-05-08 | Арадайм Корпорейшн | Липосомы, в которых образуются нанокристаллы лекарственного вещества после замораживания-оттаивания |
MX2016014921A (es) | 2014-05-15 | 2017-07-28 | Insmed In Incorporated | Metodos para tratar infecciones pulmonares micobacterianas no tuberculosas. |
US10245393B2 (en) | 2014-08-13 | 2019-04-02 | Elwha Llc | Methods, systems, and devices related to a supplemental inhaler |
US10987048B2 (en) | 2014-08-13 | 2021-04-27 | Elwha Llc | Systems, methods, and devices to incentivize inhaler use |
US10765817B2 (en) | 2014-08-13 | 2020-09-08 | Elwha, Llc | Methods, systems, and devices related to delivery of alcohol with an inhaler |
WO2016179365A1 (en) * | 2015-05-05 | 2016-11-10 | Musc Foundation For Research Development | Nanocarriers for delivery of alpha-1-antitrypsin |
TWI609701B (zh) * | 2016-01-05 | 2018-01-01 | 國立交通大學 | 滴點式複合藥物凝膠及其製備方法 |
US20170355933A1 (en) * | 2016-06-09 | 2017-12-14 | The Procter & Gamble Company | Cleaning compositions including nuclease enzyme and malodor reduction materials |
EA031933B1 (ru) * | 2016-08-05 | 2019-03-29 | Общество С Ограниченной Ответственностью "Научно-Производственный Центр Пробиотех" | Ветеринарный биопрепарат, способ его получения (варианты) и способ лечения нодулярного дерматита крупного рогатого скота (варианты) |
US10707531B1 (en) | 2016-09-27 | 2020-07-07 | New Dominion Enterprises Inc. | All-inorganic solvents for electrolytes |
WO2018094253A1 (en) | 2016-11-18 | 2018-05-24 | Pacira Pharmaceuticals, Inc. | Zinc meloxicam complex microparticle multivesicular liposome formulations and processes for making the same |
EP3768270A4 (en) * | 2018-03-19 | 2021-12-08 | Sheo Pharmaceuticals | METHODS AND COMPOSITIONS FOR TREATING IDIOPATHIC PULMONARY FIBROSIS |
US11571386B2 (en) | 2018-03-30 | 2023-02-07 | Insmed Incorporated | Methods for continuous manufacture of liposomal drug products |
JP7391039B2 (ja) | 2018-04-23 | 2023-12-04 | インスパーメッド コーポレーション | 肺疾患の処置に使用するための吸入可能なリポソーム徐放性組成物 |
CN111249251A (zh) * | 2018-12-03 | 2020-06-09 | 华中农业大学 | 一种恩诺沙星壳聚糖纳米粒 |
US20220117893A1 (en) * | 2019-02-22 | 2022-04-21 | The Blue Group Llc | Inhalable therapeutic agent |
US20220249375A1 (en) * | 2019-06-28 | 2022-08-11 | Jiangsu Hengrui Medicine Co., Ltd. | Sustained-release lipid composition and preparation method therefor |
CN113018443B (zh) * | 2019-12-27 | 2022-09-13 | 海南斯达制药有限公司 | 治疗呼吸系统疾病的药物组合物及其制备方法 |
CN113116823B (zh) * | 2019-12-30 | 2024-02-20 | 江苏恒瑞医药股份有限公司 | 一种脂质体及其制备方法 |
CN111420024B (zh) * | 2020-04-07 | 2023-10-03 | 中国科学院深圳先进技术研究院 | 杆菌酞a在制备预防和治疗冠状病毒的药物中的应用 |
CN112076193B (zh) * | 2020-10-13 | 2021-10-26 | 苏州大学 | 甲氧喹酸在制备用于治疗和/或预防以t-型钙通道为治疗靶点的疾病的药物中的应用 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2215716C (en) * | 1997-09-17 | 1999-12-07 | Her Majesty The Queen, In Right Of Canada, As Represented By The Ministe R Of National Defence | Aerosol delivery of liposome-encapsulated fluoroquinolone |
CN1295465A (zh) * | 1998-04-02 | 2001-05-16 | 阿尔扎有限公司 | 脂质体组合物和喹诺酮的给药方法 |
CN1332626A (zh) * | 1998-11-12 | 2002-01-23 | 弗兰克G·皮尔基威克兹 | 一种吸入给药系统 |
CN1747738A (zh) * | 2002-10-29 | 2006-03-15 | 川塞夫有限公司 | 缓释抗感染剂 |
Family Cites Families (54)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2000414A (en) | 1932-08-10 | 1935-05-07 | Ig Farbenindustrie Ag | Explosive composition |
US4142026A (en) | 1977-04-22 | 1979-02-27 | Zordan Macario J | Dry cell adapter |
DE2848503C2 (de) | 1978-11-08 | 1983-05-05 | Alcan Aluminiumwerk Nürnberg GmbH, 6000 Frankfurt | Maschinengehäuse mit einem eine relativ geringe Wandstärke aufweisenden Bauteil |
US4256737A (en) | 1979-06-11 | 1981-03-17 | Syntex (U.S.A.) Inc. | Long acting depot injectable formulations for LH-RH analogues |
US4304767A (en) | 1980-05-15 | 1981-12-08 | Sri International | Polymers of di- (and higher functionality) ketene acetals and polyols |
US4507466A (en) | 1983-01-07 | 1985-03-26 | The Dow Chemical Corporation | Dense star polymers having core, core branches, terminal groups |
US6759057B1 (en) | 1986-06-12 | 2004-07-06 | The Liposome Company, Inc. | Methods and compositions using liposome-encapsulated non-steroidal anti-inflammatory drugs |
WO1995024221A1 (en) | 1986-08-18 | 1995-09-14 | The Dow Chemical Company | Bioactive and/or targeted dendrimer conjugates |
DE3786000T3 (de) | 1986-08-18 | 1997-08-21 | Dow Chemical Co | Conjugate dichter Sterne. |
US4957998A (en) | 1988-08-22 | 1990-09-18 | Pharmaceutical Delivery Systems, Inc. | Polymers containing acetal, carboxy-acetal, ortho ester and carboxyortho ester linkages |
US4938763B1 (en) | 1988-10-03 | 1995-07-04 | Atrix Lab Inc | Biodegradable in-situ forming implants and method of producing the same |
US5006343A (en) | 1988-12-29 | 1991-04-09 | Benson Bradley J | Pulmonary administration of pharmaceutically active substances |
ATE92107T1 (de) | 1989-04-29 | 1993-08-15 | Delta Biotechnology Ltd | N-terminale fragmente von menschliches serumalbumin enthaltenden fusionsproteinen. |
FR2650598B1 (fr) | 1989-08-03 | 1994-06-03 | Rhone Poulenc Sante | Derives de l'albumine a fonction therapeutique |
US6623671B2 (en) | 1990-10-05 | 2003-09-23 | Royden M. Coe | Liposome extrusion process |
CA2079444C (en) | 1991-02-14 | 2004-02-03 | Rimona Margalit | Binding of recognizing substances to liposomes |
US5176907A (en) | 1991-08-13 | 1993-01-05 | The Johns Hopkins University School Of Medicine | Biocompatible and biodegradable poly (phosphoester-urethanes) |
FR2686899B1 (fr) | 1992-01-31 | 1995-09-01 | Rhone Poulenc Rorer Sa | Nouveaux polypeptides biologiquement actifs, leur preparation et compositions pharmaceutiques les contenant. |
FR2686901A1 (fr) | 1992-01-31 | 1993-08-06 | Rhone Poulenc Rorer Sa | Nouveaux polypeptides antithrombotiques, leur preparation et compositions pharmaceutiques les contenant. |
US6890555B1 (en) | 1992-02-05 | 2005-05-10 | Qlt, Inc. | Liposome compositions of porphyrin photosensitizers |
US5497763A (en) | 1993-05-21 | 1996-03-12 | Aradigm Corporation | Disposable package for intrapulmonary delivery of aerosolized formulations |
US5367051A (en) | 1993-07-22 | 1994-11-22 | Sri International | Amine-containing polymerizable monomers and polymers functionalized with fullerenes to provide polymers with high temperature stability |
CA2101241C (en) | 1993-07-23 | 1998-12-22 | Jonathan P. Wong | Liposome-encapsulated ciprofloxacin |
CA2153251C (en) | 1993-11-05 | 1998-09-01 | David Samuel Collins | Liposome preparation and material encapsulation method |
SE518578C2 (sv) | 1994-06-15 | 2002-10-29 | Gs Dev Ab | Lipidbaserad komposition |
EP0825852B1 (en) * | 1995-04-18 | 2004-07-07 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Liposome drug-loading method and composition |
US5747058A (en) | 1995-06-07 | 1998-05-05 | Southern Biosystems, Inc. | High viscosity liquid controlled delivery system |
US5968543A (en) | 1996-01-05 | 1999-10-19 | Advanced Polymer Systems, Inc. | Polymers with controlled physical state and bioerodibility |
EP0914094A4 (en) | 1996-03-28 | 2000-03-01 | Univ Illinois | MATERIALS AND METHOD FOR PRODUCING IMPROVED LIPOSOMAL AGENTS |
CA2174803C (en) | 1996-04-23 | 2000-07-11 | Jonathan P. Wong | Use of liposome encapsulated ciprofloxacin as an immunotherapeutic drug |
GB9609779D0 (en) | 1996-05-10 | 1996-07-17 | Univ Bruxelles | Freeze dried liposome encapsulated amphiphilic drug compositions and a process for the preparation thereof |
US6770291B2 (en) | 1996-08-30 | 2004-08-03 | The United States Of America As Represented By The Department Of Health And Human Services | Liposome complexes for increased systemic delivery |
US6056973A (en) | 1996-10-11 | 2000-05-02 | Sequus Pharmaceuticals, Inc. | Therapeutic liposome composition and method of preparation |
US6541606B2 (en) | 1997-12-31 | 2003-04-01 | Altus Biologics Inc. | Stabilized protein crystals formulations containing them and methods of making them |
BR9911071A (pt) * | 1998-05-27 | 2001-02-06 | Euro Celtique Sa | Preparações para aplicação de agentes antiinflamatórios, especialmente anti-sépticos e/ou agentes promotores da cura de feridas no trato respiratório superior e/ou no ouvido |
ATE428371T1 (de) | 1998-07-17 | 2009-05-15 | Pacira Pharmaceuticals Inc | Biologisch abbaubare anordnungen zur kontrollierten freigabe eingeschlossener substanzen |
US6855296B1 (en) | 1998-11-13 | 2005-02-15 | Optime Therapeutics, Inc. | Method and apparatus for liposome production |
WO2000029103A1 (en) | 1998-11-13 | 2000-05-25 | Optime Therapeutics, Inc. | Method and apparatus for liposome production |
AU1249001A (en) | 1999-06-11 | 2001-01-31 | Nektar Therapeutics Al, Corporation | Hydrogels derived from chitosan and poly(ethylene glycol) or related polymers |
AU780194B2 (en) | 1999-06-24 | 2005-03-10 | Kyowa Hakko Kirin Co., Ltd. | Method of regulating leakage of drug encapsulated in liposomes |
US6392008B1 (en) | 1999-07-21 | 2002-05-21 | The Penn State Research Foundation | Polyphosphazene polymers |
DE19954843C2 (de) | 1999-11-09 | 2003-11-20 | Novosom Ag | Verfahren zur Verkapselung von Proteinen oder Peptiden in Liposomen, mit dem Verfahren hergestellte Liposomen und deren Verwendung |
US6946134B1 (en) | 2000-04-12 | 2005-09-20 | Human Genome Sciences, Inc. | Albumin fusion proteins |
WO2002092661A1 (en) | 2001-05-11 | 2002-11-21 | Ap Pharma, Inc. | Peg-poe, peg-poe-peg, and poe-peg-poe block copolymers |
JP2005525375A (ja) | 2002-03-05 | 2005-08-25 | トランセイブ, インク. | 生物活性物質をリポソーム又は脂質複合体内に封入する方法 |
US7718189B2 (en) | 2002-10-29 | 2010-05-18 | Transave, Inc. | Sustained release of antiinfectives |
US7879351B2 (en) | 2002-10-29 | 2011-02-01 | Transave, Inc. | High delivery rates for lipid based drug formulations, and methods of treatment thereof |
KR20060015265A (ko) | 2003-05-30 | 2006-02-16 | 알자 코포레이션 | 제제의 폐 투여 방법 |
FR2856844B1 (fr) | 2003-06-24 | 2006-02-17 | Commissariat Energie Atomique | Circuit integre sur puce de hautes performances |
EP1525890A1 (en) | 2003-10-02 | 2005-04-27 | Complex Biosystems GmbH | Protein-Proteophore complexes |
JP2008504012A (ja) | 2004-01-28 | 2008-02-14 | シントニックス・ファーマシューティカルズ・インコーポレーテッド | 不妊治療のためのへテロ二量体卵胞刺激ホルモン−Fc(FSH−Fc)融合タンパク質 |
CA2838111C (en) * | 2005-12-08 | 2016-01-19 | Insmed Incorporated | Lipid-based compositions of antiinfectives for treating pulmonary infections and methods of use thereof |
US8119156B2 (en) | 2006-10-24 | 2012-02-21 | Aradigm Corporation | Dual action, inhaled formulations providing both an immediate and sustained release profile |
US8268347B1 (en) * | 2006-10-24 | 2012-09-18 | Aradigm Corporation | Dual action, inhaled formulations providing both an immediate and sustained release profile |
-
2007
- 2007-10-22 US US11/876,539 patent/US8268347B1/en active Active
- 2007-10-23 PT PT78672607T patent/PT2079443E/pt unknown
- 2007-10-23 EP EP14165088.7A patent/EP2759292A1/en not_active Withdrawn
- 2007-10-23 EP EP14175442.4A patent/EP2789330A1/en not_active Withdrawn
- 2007-10-23 CN CNA2007800395875A patent/CN101553209A/zh active Pending
- 2007-10-23 DK DK07867260.7T patent/DK2079443T3/en active
- 2007-10-23 AU AU2007322224A patent/AU2007322224B2/en not_active Ceased
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- 2007-10-23 ES ES07867260.7T patent/ES2520028T3/es active Active
- 2007-10-23 EP EP07867260.7A patent/EP2079443B1/en not_active Not-in-force
- 2007-10-23 WO PCT/US2007/022424 patent/WO2008063341A2/en active Application Filing
- 2007-10-23 SI SI200731557T patent/SI2079443T1/sl unknown
- 2007-10-23 CA CA2667494A patent/CA2667494C/en active Active
- 2007-10-23 PL PL07867260T patent/PL2079443T3/pl unknown
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2012
- 2012-07-13 US US13/549,039 patent/US8414915B2/en active Active
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2215716C (en) * | 1997-09-17 | 1999-12-07 | Her Majesty The Queen, In Right Of Canada, As Represented By The Ministe R Of National Defence | Aerosol delivery of liposome-encapsulated fluoroquinolone |
CN1295465A (zh) * | 1998-04-02 | 2001-05-16 | 阿尔扎有限公司 | 脂质体组合物和喹诺酮的给药方法 |
CN1332626A (zh) * | 1998-11-12 | 2002-01-23 | 弗兰克G·皮尔基威克兹 | 一种吸入给药系统 |
CN1747738A (zh) * | 2002-10-29 | 2006-03-15 | 川塞夫有限公司 | 缓释抗感染剂 |
Also Published As
Publication number | Publication date |
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EP2759292A1 (en) | 2014-07-30 |
PT2079443E (pt) | 2014-11-26 |
CA2667494C (en) | 2015-05-19 |
AU2007322224B2 (en) | 2012-05-17 |
JP2010507658A (ja) | 2010-03-11 |
JP5254239B2 (ja) | 2013-08-07 |
PL2079443T3 (pl) | 2015-02-27 |
CA2667494A1 (en) | 2008-05-29 |
CN104666248A (zh) | 2015-06-03 |
EP2789330A1 (en) | 2014-10-15 |
CN101553209A (zh) | 2009-10-07 |
SI2079443T1 (sl) | 2014-12-31 |
EP2079443B1 (en) | 2014-08-27 |
WO2008063341A3 (en) | 2008-10-16 |
US20120244206A1 (en) | 2012-09-27 |
DK2079443T3 (en) | 2014-12-08 |
JP2013116909A (ja) | 2013-06-13 |
WO2008063341A2 (en) | 2008-05-29 |
ES2520028T3 (es) | 2014-11-11 |
EP2079443A2 (en) | 2009-07-22 |
AU2007322224A1 (en) | 2008-05-29 |
JP5797217B2 (ja) | 2015-10-21 |
US8414915B2 (en) | 2013-04-09 |
EP2079443A4 (en) | 2012-03-07 |
US20120282328A1 (en) | 2012-11-08 |
US8268347B1 (en) | 2012-09-18 |
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